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Exploiting stem-cell derived epithelia to investigate pharmacological repair of bicarbonate transport in cystic fibrosis


   UCL Division of Biosciences

  Dr Marcel Bijvelds  Sunday, December 11, 2022  Funded PhD Project (Students Worldwide)

About the Project

The cystic fibrosis transmembrane conductance regulator (CFTR) anion channel mediates chloride and bicarbonate secretion across various epithelia in the body. Bicarbonate is essential for optimal function of various luminal secretions. As a result, people with cystic fibrosis (CF), i.e. people with little or no CFTR activity, suffer symptoms affecting many organ systems. The development of CFTR modulator drugs has transformed the care of many people with CF. These drugs are divided in two categories: (1) potentiators that improve the ion-channel function of CFTR, and (2) correctors that increase the amount of CFTR at the plasma membrane. So far, development of these has been driven by assays monitoring compound-induced changes in chloride permeation, whereas restoration of bicarbonate transport is seldom taken into account. However, it is conceivable that CF-causing mutations will have distinct consequences for chloride and bicarbonate transport, and that modulators have different effects on CFTR-mediated bicarbonate vs. chloride transport. Also, it is largely unclear whether CFTR modulators can restore bicarbonate secretion in all CF-affected tissues, in particular those that are rarely used as model systems in drug development (e.g. biliary epithelium). The aim of this project is to increase our knowledge of CFTR-dependent bicarbonate secretion, in the hope that a better understanding of its role in the pathophysiology of the disease may ultimately improve pharmacological treatment of people with CF. In this project, we will use advanced stem-cell, biochemical, molecular biology and genomics-based technologies to investigate epithelial bicarbonate secretion and luminal pH regulation, and use the organoid platform to develop new methods to assess (CFTR-dependent) bicarbonate secretion in CF-affected gastro-intestinal tissues, and to assess the effect of modulator therapy on CFTR function.

The PhD studentship is available to start in early 2023. Informal enquiries can be sent to Dr Marcel Bijvelds ().

For more information see also https://www.erasmusmc.nl/en/research/departments/gastroenterology-hepatology

You can view more PhD studentships here: https://www.findaphd.com/phds/program/4-fully-funded-interdisciplinary-phd-studentships/?p5828


Funding Notes

The grant provides for a salary of between €36,564-€40,032 per year, and covers the costs of tuition fees, laboratory reagents and materials. Funds are also available for training, travel and conference visits.

References

Ciciriello F, Bijvelds MJC, Alghisi F, Meijsen KF, Cristiani L, Sorio C, et al. Theratyping of the rare CFTR variants E193K and R334W in rectal organoid-derived epithelial monolayers. J Pers Med. 2022;12(4).
Bijvelds MJC, Roos FJM, Meijsen KF, Roest HP, Verstegen MMA, Janssens HM, et al. Rescue of chloride and bicarbonate transport by elexacaftor-ivacaftor-tezacaftor in organoid-derived CF intestinal and cholangiocyte monolayers. J Cyst Fibros. 2021.

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